The goal of this project is to understand the process of cell loss in the brains of individuals with Huntington's disease (HD) and the relationship of the symptomatology to progressive changes in the functional circuitry of the basal ganglia, allowing a more rationale approach to appropriate pharmacotherapy at different clinical stages of the disease. These studies will investigate, in autopsy brain tissue from patients with HD and in animal models, the underlying cause of chorea, and proposed pathogenetic mechanisms, giving insight into possible preventing pharmacotherapy aimed at slowing the progress of the disease. Hypotheses to be evaluated include: that chorea is related to striosomal neuronal loss in the neostriatum; that changes in functional circuitry produced by striosomal neuronal loss produce predicted changes in basal ganglia circuits in early HD and that similar changes occur in an animal model of the hyperdopaminergic state; that relative striosomal vulnerability may be related to molecular characteristics of striosomal vs. matrix neurons in normal human brain and in HD; that modified animal models of HD will show the relative vulnerability of striosomes; and that a new animal model of HD using excitotoxic and metabolic toxins in organotypic cultures of rat striatum can be developed that will provide an improved preparation for future research studies on toxic mechanisms and the basal ganglia. These studies will provide a new framework for thinking about the basis of clinical symptomatology in HD, pathogenetic mechanisms in HD, the effects of the abnormal gene, a new standard for animal models of HD, and a new basis for the design of pharmacotherapy in HD.